a broad range of SARS-CoV-2 inhibitor

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on long term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We here have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma and Epsilon, at picomolar ranges of IC50 in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by co-treatment in K18-hACE2-transgenic mice, accompanying with a significant prevention of virus-associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggests that C6G25S provides an alternative and effective approach to combating the COVID-19 pandemic.严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）变异株的出现改变了新冠（COVID-19）大流行的走向，也为疫苗策略的长期有效性带来了诸多不确定性。开发可覆盖多种SARS-CoV-2变异株的新型治疗手段已刻不容缓。本研究设计了一种可吸入式小干扰核糖核酸（small interfering RNA, siRNA）C6G25S，该序列可覆盖目前99.8%的SARS-CoV-2变异株，且在体外实验中能以皮摩尔级的半最大效应浓度（half maximal inhibitory concentration, IC50）抑制包括Alpha、Delta、Gamma、Epsilon在内的主流毒株。此外，通过预防性给药，C6G25S可完全抑制肺部感染性病毒粒子的产生；在K18-hACE2转基因小鼠模型中，联合给药则能使病毒粒子载量降低96.2%，同时显著改善病毒引发的广泛肺泡损伤、血管血栓及免疫细胞浸润等病理改变。本研究数据表明，C6G25S为对抗新冠大流行提供了一种高效可行的替代方案。